NUP85 alleviates lipid metabolism and inflammation by regulating PI3K/AKT signaling pathway in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the common causes of chronic liver disease in the world. The problem of NAFLD had become increasingly prominent. However, its pathogenesis is still indistinct. As we all know, NAFLD begins with the accumulation of triglyceride (TG), leading to fatty degeneration, inflammation and other liver tissues damage. Notably, structure of nucleoporin 85 (NUP85) is related to lipid metabolism and inflammation of liver diseases. In this study, the results of researches indicated that NUP85 played a critical role in NAFLD. Firstly, the expression level of NUP85 in methionine-choline-deficient (MCD)-induced mice increased distinctly, as well as the levels of fat disorder and inflammation. On the contrary, knockdown of NUP85 had the opposite effects. In vitro, AML-12 cells were stimulated with 2 mm free fatty acids (FFA) for 24 h. Results also proved that NUP85 significantly increased in model group, and increased lipid accumulation and inflammation level. Besides, NUP85 protein could interact with C-C motif chemokine receptor 2 (CCR2). Furthermore, when NUP85 protein expressed at an extremely low level, the expression level of CCR2 protein also decreased, accompanied with an inhibition of phosphorylation of phosphoinositol-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway. What is more, trans isomer (ISRIB), a targeted inhibitor of NUP85, could alleviate NAFLD. In summary, our findings suggested that NUP85 functions as an important regulator in NAFLD through modulation of CCR2.

The tumor burden score may be a discriminator in microwave ablation versus liver resection for hepatocellular carcinoma within the Milan criteria: a propensity score matching and inverse probability of treatment weighting study.

Purpose: This study aims to compare the prognostic outcome of resection (RES) and microwave ablation (MWA) in different tumor burden score (TBS) cohorts. Patients and Methods: We retrospectively analyzed 479 patients with primary hepatocellular carcinoma (HCC) who underwent RES (n = 329) or MWA (n = 150) with curative intent at our institution. We assessed their overall survival (OS) and progression-free survival (PFS) using the Kaplan-Meier curve. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to minimize selection and confounding biases. Multivariate Cox regression was used to define the association between surgical modalities and outcomes. Results: Following PSM, in the TBS ≤3 cohort, the cumulative 1-, 3-, 5- year OS in the RES and MWA groups were 92.5% vs. 98.8%, 82.7% vs. 90.0%, and 82.7% vs. 83.2% (P = 0.366), respectively. The corresponding PFS rates in the RES and MWA groups were 82.7% vs. 88.0%, 63.6% vs. 68.3% and 55.2% vs. 56.3, respectively (P = 0.218). In the TBS >3 cohort, the cumulative 1-, 3-, 5- year OS between the RES and MWA groups were 92.5% vs. 95.0%, 82.8% vs. 73.2% and 76.3% vs. 55.1%, (P = 0.034), respectively. The corresponding PFS rates in the RES and MWA groups were 78.0% vs. 67.5%, 63.6% vs. 37.5% and 55.2% vs. 37.1%, respectively (P = 0.044). The IPTW analysis showed similar results as shown in PSM analysis. The multivariate Cox regression indicated that the type of surgical modality was not associated with a poorer prognostic outcome in the TBS ≤3 cohort, unlike in the TBS >3 cohort. Conclusion: TBS, as a discriminator, might help guide treatment decision-making for HCC within the Milan criteria.

Manganese-catalyzed Efficient Synthesis of N-heterocycles and Aminoketones Using Glycerol as a C3 Synthon.

Glycerol is one of the important biomass-derived feedstocks and the high-value utilizations of glycerol have attracted much attentions in recent years. Herein, we report a manganese catalyzed dehydrogenative coupling of glycerol with amines for the synthesis of substituted 2-methylquinoxalines, 2-ethylbenzimidazoles, and α-aminoketones without any external oxidant. In these reactions, NHC-based pincer manganese complex featuring a pyridine backbone displayed high catalytic activity and selectivity, in which hydrogen and water were produced as the only by-products using glycerol as a C3 synthon.

A Tailored Versatile and Efficient NHC-Based NNC-Pincer Manganese Catalyst for Hydrogenation of Polar Unsaturated Compounds.

The reactivity of metal-hydride complexes can be harnessed by the modification of ancillary ligands. With the aim of improving the hydride-donor ability of the key Mn-H intermediate and reducing steric hindrance, we herein report the rational design of a versatile and efficient NHC-based NNC-pincer Mn catalyst for hydrogenation reactions. This newly developed catalyst exhibited higher activity than the corresponding NNP-pincer Mn catalyst owing to its reduced steric hindrance and enhanced Mn-H σ-bonding orbital energy level through a π-antibonding interaction. Using this highly active NNC-pincer Mn catalyst, a rich array of polar unsaturated compounds (>80 examples) including esters, N-heteroarenes, amides, carbonates, and urea derivatives, were successfully hydrogenated under relatively mild conditions. This work represents a rare example of a general phosphine-free Mn-catalyzed hydrogenation system.

Effect of Hydrothermal Method Temperature on the Spherical Flowerlike Nanostructures NiCo(OH)4-NiO.

NiCo(OH)4-NiO composite electrode materials were prepared using hydrothermal deposition and electrophoretic deposition. NiCo(OH)4 is spherical and flowerlike, composed of nanosheets, and NiO is deposited on the surface of NiCo(OH)4 in the form of nanorods. NiCo(OH)4 has a large specific surface area and can provide more active sites. Synergistic action with NiO deposits on the surface can provide a higher specific capacitance. In order to study the influence of hydrothermal reaction temperature on the properties of NiCo(OH)4, the prepared materials of NiCo(OH)4-NiO, the hydrothermal reaction temperatures of 70 °C, 90 °C, 100 °C, and 110 °C were used for comparison. The results showed that the NiCo(OH)4-NiO-90 specific capacitance of the prepared electrode material at its maximum when the hydrothermal reaction temperature is 90 °C. The specific capacitance of the NiCo(OH)4-NiO-90 reaches 2129 F g-1 at the current density of 1 A g-1 and remains 84% after 1000 charge-discharge cycles.

Therapeutic efficacy of microwave coagulation versus liver resection for hepatocellular carcinoma within the Milan criteria: A propensity score matching analysis.

INTRODUCTION: This study aimed to compare the therapeutic efficacy of resection (RES) and microwave ablation (MWA) for hepatocellular carcinoma (HCC) within the Milan criteria. MATERIALS AND METHODS: Between 2011 and 2019, 426 HCC patients within the Milan criteria were treated at our institution (RES: n = 291; MWA: n = 135). We compared overall survival (OS), disease-free survival (DFS), complications, and hospital stay in these patients using propensity score matching (PSM) and determined the prognostic factors using multivariate Cox analysis. RESULTS: Following 1:1 matching using PSM, 121 patients were matched in each group. The 1-, 3-, and 5-year OS rates were 98.3%, 84.7%, and 69.6% for the MWA group and 96.5%, 81.8%, and 78.1% for the RES group (p = 0.667). The corresponding DFS rates for the MWA and RES groups were 81.8%, 54.4%, and 42.3% and 85.4%, 67.8%, and 57.9%, respectively (p = 0.174). The MWA group had less blood loss and shorter hospital stays (both p < 0.001) than the RES group. CONCLUSION: MWA resulted in survival outcomes that were similar to those of RES for HCC within the Milan criteria. However, it had more favorable hospital stay and blood loss outcomes than RES.

Deletion of p38γ attenuates ethanol consumption- and acetaminophen-induced liver injury in mice through promoting Dlg1.

Acetaminophen (APAP) is one of the major causes of drug-induced acute liver injury, and ethanol may aggravate APAP-induced liver injury. The problem of ethanol- and APAP-induced liver injury becomes increasingly prominent, but the mechanism of ethanol- and APAP-induced liver injury remains ambiguous. p38γ is one of the four isoforms of P38 mitogen activated protein kinases, that contributes to inflammation in different diseases. In this study we investigated the role of p38γ in ethanol- and APAP-induced liver injury. Liver injury was induced in male C57BL/6 J mice by giving liquid diet containing 5% ethanol (v/v) for 10 days, followed by gavage of ethanol (25% (v/v), 6 g/kg) once or injecting APAP (200 mg/kg, ip), or combined the both treatments. We showed that ethanol significantly aggravated APAP-induced liver injury in C57BL/6 J mice. Moreover, the expression level of p38γ was up-regulated in the liver of ethanol-, APAP- and ethanol+APAP-treated mice. Knockdown of p38γ markedly attenuated liver injury, inflammation, and steatosis in ethanol+APAP-treated mice. Liver sections of p38γ-knockdown mice displayed lower levels of Oil Red O stained dots and small leaky shapes. AML-12 cells were exposed to APAP (5 mM), ethanol (100 mM) or combined treatments. We showed that P38γ was markedly increased in ethanol+APAP-treated AML-12 cells, whereas knockdown of p38γ significantly inhibited inflammation, lipid accumulation and oxidative stress in ethanol+APAP-treated AML-12 cells. Furthermore, we revealed that p38γ could combine with Dlg1, a member of membrane-associated guanylate kinase family. Deletion of p38γ up-regulated the expression level of Dlg1 in ethanol+APAP-treated AML-12 cells. In summary, our results suggest that p38γ functions as an important regulator in ethanol- and APAP-induced liver injury through modulation of Dlg1.

Coicis semen protects against focal cerebral ischemia-reperfusion injury by inhibiting oxidative stress and promoting angiogenesis via the TGFß/ALK1/Smad1/5 signaling pathway.

BACKGROUND: Ischemic stroke is a devastating disease that causes long-term disability. However, its pathogenesis is unclear, and treatments for ischemic stroke are limited. Recent studies indicate that oxidative stress is involved in the pathological progression of ischemic stroke and that angiogenesis participates in recovery from ischemic stroke. Furthermore, previous studies have shown that Coicis Semen has antioxidative and anti-inflammatory effects in a variety of diseases. In the present study, we investigated whether Coicis Semen has a protective effect against ischemic stroke and the mechanism of this protective effect. RESULTS: Coicis Semen administration significantly decreased the infarct volume and mortality and alleviated neurological deficits at 3, 7 and 14 days after MCAO. In addition, cerebral edema at 3 days poststroke was ameliorated by Coicis Semen treatment. DHE staining showed that ROS levels in the vehicle group were increased at 3 days after reperfusion and then gradually declined, but Coicis Semen treatment reduced ROS levels. The levels of GSH and SOD in the brain were increased by Coicis Semen treatment, while MDA levels were reduced. Furthermore, Coicis Semen treatment decreased the extravasation of EB dye in MCAO mouse brains and elevated expression of the tight junction proteins ZO-1 and Occludin. Double immunofluorescence staining and western blot analysis showed that the expression of angiogenesis markers and TGFß pathway-related proteins was increased by Coicis Semen administration. Consistent with the in vivo results, cytotoxicity assays showed that Coicis Semen substantially promoted HUVEC survival following OGD/RX in vitro. Additionally, though LY2109761 inhibited the activation of TGFß signaling in OGD/RX model animals, Coicis Semen cotreatment markedly reversed the downregulation of TGFß pathway-related proteins and increased VEGF levels. METHODS: Adult male wild-type C57BL/6J mice were used to develop a middle cerebral artery occlusion (MCAO) stroke model. Infarct size, neurological deficits and behavior were evaluated on days 3, 7 and 14 after staining. In addition, changes in superoxide dismutase (SOD), GSH and malondialdehyde (MDA) levels were detected with a commercial kit. Blood-brain barrier (BBB) permeability was assessed with Evans blue (EB) dye. Western blotting was also performed to measure the levels of tight junction proteins of the BBB. Additionally, ELISA was performed to measure the level of VEGF in the brain. The colocalization of CD31, angiogenesis markers, and Smad1/5 was assessed by double immunofluorescent staining. TGFß pathway-related proteins were measured by western blotting. Furthermore, the cell viability of human umbilical vein endothelial cells (HUVECs) following oxygen-glucose deprivation/reoxygenation (OGD/RX) was measured by Cell Counting Kit (CCK)-8 assay. CONCLUSIONS: Coicis Semen treatment alleviates brain damage induced by ischemic stroke through inhibiting oxidative stress and promoting angiogenesis by activating the TGFß/ALK1 signaling pathway.

Peroxiredoxin-1 Overexpression Attenuates Doxorubicin-Induced Cardiotoxicity by Inhibiting Oxidative Stress and Cardiomyocyte Apoptosis.

Background. Previous research has shown that peroxiredoxin 1 (Prdx1) is an important modulator of physiological and pathophysiological cardiovascular events. This study is aimed at investigating the role and underlying mechanism of Prdx1 in doxorubicin- (DOX-) induced cardiotoxicity. Cardiac-specific expression of Prdx1 was induced in mice, and the mice received a single dose of DOX (15 mg/kg) to generate cardiotoxicity. First, our study demonstrated that Prdx1 expression was upregulated in the heart and in cardiomyocytes after DOX treatment. Second, we provided direct evidence that Prdx1 overexpression ameliorated DOX-induced cardiotoxicity by attenuating oxidative stress and cardiomyocyte apoptosis. Mechanistically, we found that DOX treatment increased the phosphorylation level of apoptosis signal-regulating kinase-1 (ASK1) and the downstream protein p38 in the heart and in cardiomyocytes, and these effects were decreased by Prdx1 overexpression. In contrast, inhibiting Prdx1 promoted DOX-induced cardiac injury via the ASK1/p38 pathway. These results suggest that Prdx1 may be an effective therapeutic option to prevent DOX-induced cardiotoxicity.

Dexmedetomidine with sufentanil in intravenous patient-controlled analgesia for relief from postoperative pain, inflammation and delirium after esophageal cancer surgery.

BACKGROUND AND AIMS: Postoperative pain can cause serious adverse reactions that severely affect postoperative outcome. The present study evaluated the effect of dexmedetomidine (DEX) added to sufentanil in intravenous patient-controlled analgesia (PCA) on the relief of pain and inflammatory responses during postoperative recovery of patients undergoing a combined thoracoscopic-laparoscopic esophagectomy (TLE). METHODS: Sixty patients undergoing TLE were randomly allocated to receive 1 µg/ml of sufentanil alone (Group S) or 1 µg/ml of sufentanil plus 2.5 µg/ml of DEX (Group D) for postoperative intravenous (IV) PCA. Postoperative pain relief, cumulative PCA requirements, inflammatory marker levels, delirium and recovery were assessed. RESULTS: A joint DEX and sufentanil regimen significantly reduced the area under the curve of numerical rating scores for pain at rest (NRSR) and coughing (NRSC) at 1-48 h postoperatively (P = 0.000) that were associated with lower PCA-delivered cumulative sufentanil consumption and less PCA frequency until 48 h postoperatively (P < 0.05 and P < 0.0001, respectively). The simultaneous administration of DEX and sufentanil significantly reduced plasma IL-6 and TNF-α concentrations and increased IL-10 level (P < 0.0001, P = 0.0003 and P = 0.0345, respectively), accompanied by better postoperative delirium categories and health statuses of patients (P = 0.024 and P < 0.05, respectively). There was no hypotension, bradycardia, respiratory depression or oversedation in Group D. CONCLUSION: Patients receiving DEX in addition to IV PCA sufentanil for TLE exhibited better postoperative analgesia, fewer inflammatory responses and lower postoperative delirium categories and better health statuses.